HD is a genetically caused brain disorder that causes uncontrollable bodily movements and robs people's ability to walk, talk, eat, and think. The final result is a slow, ugly death. Children of parents with HD have a 50-50 chance of inheriting the disease. There is no cure or treatment.

Thursday, February 26, 2015

Riding the
emotion of a keynote speech by a young scientist at risk for Huntington’s
disease, and seeking treatments with the immense help of a non-profit
foundation, the participants at a historic research conference this week
witnessed the fusion of science and human solidarity ultimately necessary for
defeating HD.

On the evening
of February 23, I and the approximately 300 attendees at the 10th Annual HD
Therapeutics Conference, sponsored by the CHDI Foundation, Inc., listened
as Jeff Carroll, Ph.D., recounted his mother’s demise from HD, his positive
test for the HD genetic mutation, and his decision to pursue a career in
science to save himself and others from HD.

“He’s an
interesting combination of things in terms of being an advocate in the
community, in terms of being someone from an HD family, in terms of being a
top-flight researcher in the HD community, in terms of being a great
communicator – he and his partner Ed Wild – in establishing HDBuzz, which
is just a tremendously useful model of how to communicate results out to the
rest of the community,” Robert Pacifici, Ph.D., CHDI’s chief scientific
officer, said in introducing Dr. Carroll at the conference in Palm Springs, CA.

As an HD
researcher-advocate who has attended all ten therapeutics conferences since
2006, Dr. Carroll offered a uniquely qualified, candid assessment of the
progress towards treatments and CHDI’s role in the process.

“Every year, I
come home revitalized and energized by the site of so many smart people working
so hard on this problem,” Dr. Carroll, 37, told the audience in the main
ballroom at the Parker Palm Springs hotel. He expressed his profound
gratitude to CHDI, which has funded his and numerous other scientists’ research.

Painful progress toward success

However,
success depends on the “efficient and timely completion of well-designed Phase
III trials with HD drugs,” Dr. Carroll continued.

“A few weeks
ago I attended a meeting at the Princeton CHDI office that included attendees
from major pharmaceutical companies currently running HD clinical trials,” he
said. “They are deeply concerned about something that would never have occurred
to me to worry about, which is poor recruitment for trials of Huntington’s
disease drugs.

“On
reflection, it makes sense that the HD community may be wary of the way we have
been speaking to them. Participating in the first clinical trial of a new
molecule might be exciting, but participants of the third could be excused for
having some questions.”

Trial
administrators put participants through a daunting number of tests, he observed,
which may discourage people from participating in more than one trial. Because
trials are extremely expensive, sponsors often try to maximize the findings in
Phase II, but not enough trials are reaching Phase III, he added.

“It must be
said the scale of what is possible here must be unique in human history,” Dr.
Carroll said of the efforts by CHDI, which has put more than $700 million
towards treatments. “Resources on the scale being deployed by CHDI have been
spent on common diseases, but never before have they been spent on such a
focused attempt to ameliorate a rare disease.”

The HD
community will achieve “something never done before” or “fail majestically,” he
quipped with irony.

After Dr.
Carroll and his wife Meghan had HD-free twins, thanks to preimplantation genetic diagnosis (PGD), he believed that “HD is done killing people in
my family until I am gone,” he recalled.

However,
recently two at-risk babies were born in his extended family.

“For a brief window,
my family was the last that had to face this awful threat,” Dr. Carroll said.
“But the arrival of these children has reminded me that none of us are free
until we are all free.”

We must “raise
up those of our brothers and sisters still suffering,” he concluded.

Like me, Dr.
Carroll is racing against the genetic clock.

Crying for our community

This
conference, my fifth, has proved especially poignant for me personally – even
more so than the 2011 meeting, which I keynoted. In terms of the quest
for HD treatments, it has been a landmark event. (My next article will
provide an overview of the conference’s scientific aspects.)

I was both
deeply saddened and heartened by Dr. Carroll’s story. I relived my own mother’s
death from HD in 2006, my positive test for the gene in 1999, and my daughter’s
negative test for HD in the womb (PGD was unavailable) in 2000.

It was one of
the best speeches I have heard in two decades of observing the HD movement. Dr.
Carroll tempered his enthusiasm and compassion for the HD community with
hard-nosed, no-nonsense scientific analysis.

For the
evening of February 25, the conference organizers arranged for a surprise outdoor
screening of the 28-minute documentary The
Lion’s Mouth Opens, about actress, director, and producer Marianna Palka’s
positive test for HD. The film made the 2015 Academy Awards shortlist for Best
Documentary Short.

As part of the
surprise, Marianna, whom I had met earlier in the day, took questions from the
audience. She appeared at the edge of the crowd, next to me, just as the film
was ending.

It was a
highly emotional experience for me. Filled with anger, frustration, and
overwhelming sadness that a young person like Marianna should have to face HD,
and once again reliving the trauma of my own HD test and the excruciating
experience of testing our daughter, I hugged Marianna and cried uncontrollably for
several minutes as she held and consoled me.

It’s so unjust that people have to face
HD, I thought to myself.

I hardly ever
let myself think that, trying to be strong, but at that moment I allowed myself
to do so, and also to let loose all of the powerful emotions of the conference.

I told
Marianna I was so sorry for her.

Marianna, who is just 33, was strong, telling me
that we would all work together against HD.

After the film
finished, Marianna talked with the audience about her experience of genetic
testing, her strategies for staying healthy, and her work in film. She observed
that The Lion’s Mouth Opens makes men
cry.

You can watch
Marianna’s exchange with the audience in the video below.

At the start
of the conference, I had lunched with Joe Giuliano, the CHDI director of
clinical operations in Princeton, N.J., HD advocate Jimmy Pollard,
and Chris Brown, a scientist from Evotec, a drug discovery company headquartered in Germany.

We pondered
the same critical issue raised by Dr. Carroll, and that brave advocates like
Marianna impel us to consider: how to inspire more families in the HD community to
become involved in research studies and clinical trials.

I recalled my
own speeches and blog articles about the terrible barriers to greater involvement:
ignorance, fear, denial, stigma, and family tensions.

Giuliano is
also the chief CHDI administrator for the Enroll-HD program, a global
platform, research project, and HD patient and family registry aimed at facilitating clinical trials and the
discovery of treatments. As Giulano and others have noted, it is not scientists
who cure diseases, but the patients who participate in clinical trials.

That
observation provides a fitting coda to Dr. Carroll’s speech.

And it
underscores the absolute necessity to fuse science and solidarity in the fight
against not just HD, but all diseases.

With this
article I have completed my own HD milestone: it is the 200th post in this
blog.

I am grateful
to so many: God, my wife and daughter, my HD-victimized mother Carol Serbin, my
HD-warrior father Paul Serbin, who died with a broken heart in 2009, CHDI, and
the entire HD community.

Although I
worry that my overly emotional response to the conference could signal the mood
swings characteristic of early HD onset, I am also grateful that I remain, according
to my last neurological checkup, asymptomatic.

As I prepared
to depart the conference, I pondered how the HD movement can reinforce human
solidarity and our bond with the researchers.

Monday, February 23, 2015

As the Huntington’s disease community in 2015 enters a promising
phase of clinical trials for remedies that might slow or halt the progression
of the disease, one of the world’s leading HD scientists recently took stock of
the significant progress made over the past several decades.

“The horizons for therapy were very far away,” Michael Hayden,
M.D., Ph.D., the President of Global Research and Development and Chief Scientific
Officer of Israel-based Teva Pharmaceuticals, said during a February 10,
2015, presentation about his company’s latest efforts to defeat HD.

Dr. Hayden recalled how, 40 years ago, HD was virtually unknown
in his native South Africa and many other countries. HD-afflicted people faced
stigma and were left to cope with their disease “in isolation and despair,” Dr.
Hayden remembered of his first contact with the disease as a young medical
student.

“It was just a dream then that there would be pharmaceutical
companies interested in Huntington disease,” he said. (In some countries HD is
referred to as “Huntington,” not “Huntington’s.”)

However, as Teva and other companies work towards HD treatments,
the outlook has changed dramatically.

“We are now in a place of really tremendous hope,” Dr. Hayden
declared enthusiastically. “The darkness is replaced by hope and light. At the
end of the tunnel we are seeing this light now, not only with this [Teva’s]
drug but other trials you are hearing about.”

Pridopidine was first tested in two clinical trials – in Europe
and North America – by the Danish pharmaceutical company Neurosearch. The
company, although it observed some interesting effects, did not achieve
sufficiently positive results to bring the drug to market.

That’s because the chosen “endpoint” in the study, the way of
measuring the drug’s effects, didn’t show a result significant enough for
obtaining regulatory approval, Dr. Hayden explained. Neurosearch chose only a
subset of motor symptoms as the study endpoint.

But some researchers still believed pridopidine had potential as
an HD drug. Dr. Hayden and Teva studied the overall impact of pridopidine and,
after obtaining the license for the drug from Neurosearch, have decided to run
an additional clinical trial, called Pride-HD (Pridopidine Dose Escalation in
HD). Teva is using a different endpoint, the so-called total motor score, a
measurement of all the motor
symptoms.

Dr. Hayden observed that patients in the earlier pridopidine
studies actually showed improvement in motor symptoms caused by HD such as
chorea, or involuntary movements. Pridopidine also improved eye movement
substantially, he said. It also stabilized levels of dopamine, a neurotransmitter
and hormone involved in movement control, mood, and motivation.

Patients’
depression, another telltale HD symptom, also did not worsen, Dr. Hayden noted.

Aiming for broader impact

“There may be some broader affect on other features of Huntington
disease,” he added. Additional studies of pridopidine in animals have indicated
that it brings about changes in the brain, might be “neuroprotective,” and might help with
improving thinking and feeling, he explained.

Therefore, Teva will add other key endpoints to the Pride-HD
study: cognition, mood, and quality of life. The study also will assess the
effect of dosages of pridopidine higher than those given patients in the
earlier trials.

Pridopidine
“could theoretically have some effect to change the course of the illness,” Dr.
Hayden observed. “And wouldn’t that be exciting?”

Pride-HD enrolled its first patient in April 2014 and will
continue throughout 2015. Teva aims to enroll 400 patients at 54 sites in North
America, Europe, and Australia. If the results are favorable, Teva could seek
regulatory approval for the drug in late 2016, Dr. Hayden said.

As HD specialist Dr. LaVonne Goodman noted in her February 18 commentary on the potential of pridopidine, “recruitment is not going well for
Pride-HD.[...] The bottom line is that finding new drugs for HD takes a lot of work, good trials and a long-term commitment from HD families and investigators. If we don't join this or other trials, we will never have new drugs for HD: not for ourselves or the next generation."To learn more about Pride-HD and how to participate, refer to the
above-mentioned link to the webinar or call HDSA at 800-345-4372.

Teva is also conducting a clinical trial of the drug laquinomod
for use in HD, Dr. Hayden noted. Laquinomod is thought to reduce the inflammation of
the brain in neurological disorders. Click here to learn more about the trial.

Another historic moment

As a carrier of the HD gene mutation, I listened to Dr. Hayden’s
comments on the long-term progress of HD research with great hope.

Scientists have observed that managing HD effectively likely will
require a cocktail of drugs. Pridopidine is yet another potential element in
the mix. (I have reported on many of the elements in this blog over the past
ten years. Click here and here to see recent examples.)

Having tracked the HD movement for nearly 20 years, I also
appreciated Dr. Hayden’s important reminder that the quest for effective
treatments is a lengthy process. Science and clinical trials require time and
investments of money and intellect.

I wrote this article in Palm Springs, CA, just before the start of yet
another historic mark in the HD movement: the 10th Annual HD
Therapeutics Conference, sponsored by the CHDI Foundation, Inc., at the
Parker Palm Springs hotel February 23-26. In the past I have referred to this event as the "Super Bowl" of HD research.

In Palm Springs,
I will listen to other scientists take stock of the search for HD treatments.

I also expect to witness yet further examples of researchers
replacing the darkness of Huntington’s disease with hope and light.

For yet more perspective, watch my interview with Dr. Hayden
at the 2011 HD Therapeutics Conference in the video below.

Tuesday, February 03, 2015

Huntington’s disease
patients in a recently concluded clinical trial for a potential new drug to
control the disease’s characteristic involuntary movements reported that they
“felt better” overall.

The trial showed that
the compound reduced chorea substantially and with fewer and milder side
effects than a predecessor drug, a significant step, although it does not address the cognitive and psychiatric
symptoms of HD nor attempts to be a “cure.”

Like Xenazine, the
first ever drug approved by the federal Food and Drug Administration (FDA) for
Huntington’s, SD-809 attacks chorea, the involuntary, sometimes dance-like
movements caused by HD’s devastation of the brain.

As one of its
“endpoints” (research targets), Auspex used the Patients’ Global Impression of
Change scale to measure whether patients actually felt better. The patients’
responses showed convincingly that they did, in part as a result of controlling
chorea.

“I don’t think that there’s ever been a therapy
with patients with HD that has actually demonstrated that patients actually
feel better on this type of patient assessment,” Pratik Shah, Ph.D., the Auspex
president and CEO, said in an interview at Auspex headquarters on December 23.

“This is something
that in the past not everyone has been able to appreciate: the impact of chorea
on the life of a patient. We wanted to put in an instrument that really asked
the question: ‘Does this matter to the patient? Do you feel better?’ Given the
fact that perhaps not everyone outside the HD community really understands the adverse
impact of chorea on the life of a patient and their family, this was an
important question to assess.”

The trial doctors
were asked a similar set of questions about the trial participants. “The
clinicians as well saw a favorable result here,” Dr. Shah said.

As a carrier of the
HD gene mutation who lost his mother to HD nine years ago this month, I was
thrilled to hear the news about SD-809 and to visit Auspex for the second time
in recent months. You can watch my reaction in the video below.

“We saw a 37
percentage-point improvement in the SD-809 arm and 16-percent improvement in
the placebo arm, so it’s 21 percentage points above placebo,” Dr. Shah said.
“This is very robust, when you look at all the historical data [from the
Xenazine trial].”

Dr. Shah pointed out that the data are the sum of all the observations made on and by the participants.

“One person can have a two- or three-point reduction and experience great benefit, while a different individual may have the need for a greater numerical reduction,” he said.

According to one analyst who compared the two compounds, the reduction in chorea is about the
same seen in the Xenazine trial.

However, SD-809 had
fewer and far milder side effects than Xenazine. Both are taken as a pill.
Neither attacks the root causes of HD, nor the psychiatric and cognitive
symptoms that devastate most HD patients. So such drugs are not a “cure.”

Referring to the
study data, cited in a press release on the Auspex website, Dr. Shah
affirmed that SD-809 caused low levels of side effects such as depression, restlessness,
anxiety, insomnia, sleepiness, irritability, and fatigue. SD-809 caused no problems with swallowing in any of
the patients –2.2% of those trial
participants on placebo did
experience difficulty with swallowing.

The minimal level of
those side effects is important in HD, because the disease itself often causes
such symptoms, in particular depression, which appeared to be lower in the
SD-809 arm compared to placebo, Dr. Shah noted.

Pratik Shah, Ph.D. (photo by Gene Veritas)

In an assessment of
the total motor (movement) score of the standard HD disease rating scale,
SD-809 led to improvement
– an outcome lacking in the Xenazine trial, Dr. Shah pointed out.

The improvement in
this score suggests that movement problems other than chorea could be
improving, he added.

Yet another trial
measurement showed that participants’ “physical functioning” improved with SD-809, that is, movement required
to do daily tasks such as walking and climbing stairs.

SD-809 as seen by HD
experts

Ninety individuals
took part in the Phase III trial, called First-HD, at 34 sites across the U.S.
and Canada. Half received SD-809, half a placebo. All participants had at least moderate chorea. The study was double-blinded:
neither doctors nor participants knew who was receiving the drug. This is the
most rigorous form of clinical trial. Auspex ran the trial in conjunction with
the Huntington Study Group (HSG).

None of the First-HD
participants was taking Xenazine at the time of the trial. Auspex and the HSG also
conducted a trial known as ARC-HD to study another group of participants
already taking Xenazine but who switched the next day to SD-809 for the trial.
ARC-HD demonstrated that the switch between drugs did not affect the reduction
in chorea and occurred with no serious side effects. In fact, patients shifting
to SD-809 had somewhat less chorea, and at smaller dosages, Dr. Shah noted.

“New, safe and
tolerable therapies for chorea treatment are clearly needed to make this
disease an increasingly treatable condition,” said Samuel A. Frank, M.D., an
HSG researcher and principal investigator for First-HD, in the Auspex press
release. “The primary and secondary efficacy results from this study were
confirmed by the Huntington Study Group independent analysis. These clear and
unequivocal results are clinically meaningful and suggest that SD-809 may play
an important role in the treatment of Huntington's disease symptoms.”

Dr. LaVonne Goodman,
the founder of the Huntington’s Disease Drug Works program and a
clinician who has attended to scores of HD patients, echoed the optimistic
conclusions about SD-809’s efficacy.

“This drug treats
chorea with many fewer side effects associated with tetrabenazine [Xenazine],”
she wrote. “And
most important it improved quality of life.[…] If this drug lives up to the
press release, it could/should replace antipsychotic drugs as primary treatment
of chorea in Huntington's disease.”

Although not yet
convinced that SD-809 is better than Xenazine overall, the researcher-written
website HDBuzz.net affirmed in a generally positive article that the “very
well-run” Auspex trials “prove
that SD-809 could be a useful new tool to help fight excessive movements in
Huntington’s disease.”

How it works

Xenazine’s scientific
name is tetrabenazine, a drug discovered in the 1950s. HD-affected individuals
used tetrabenazine for decades in Europe and Canada, where U.S. families
purchased the drug on an individual basis in person or through mail order. Only
in 2008 did it receive FDA approval.

Chemically SD-809 is
an improvement on Xenazine. It is deutetrabenazine:
a molecule with atoms of deuterium (heavy hydrogen) attached.

“We used in select
places deuterium as a building block,” Dr. Shah explained, pointing to a model
of SD-809 made by an Auspex scientist.

Dr. Shah explains the structure of SD-809 using a
model built by an Auspex scientist. The colors represent the compound’s five
atoms: carbon (black), hydrogen (white), oxygen (red), nitrogen (blue), and
deuterium (green). In scientific terms, SD-809 (deutetrabenazine) is a VMAT2
inhibitor. (photo by Gene Veritas)

Very much like
Xenazine, SD-809 inhibits certain chemical actions in the brain in order to
avoid such symptoms as excess dopamine, which can lead to the involuntary
movements of HD, Dr. Shah explained.

He added that the
addition of deuterium “enabled this molecule to be broken down in the body more
slowly and so it sticks around longer.” As a result, the levels of the drug in
the bloodstream become “smoother.”

For patients, this
means smaller, less frequent dosages and potentially a more optimal performance
of the drug, he said.

Applying to the FDA

After the conclusion
of First-HD and ARC-HD, over 90 percent of the trial participants (excluding a few who dropped out) entered a follow-up
study so that Auspex can further analyze the effectiveness of SD-809 and the
compound’s side effects. This ongoing study gives participants access to the
compound, including those who were receiving the placebo during the trial.

On January 12, Auspex
released additional good news resulting from its ongoing analysis of SD-809:
whereas Xenazine’s instructions warn about the possibility of an abnormal,
prolonged heartbeat, SD-809 does not cause such a symptom to the point of
medical concern.

Dr. Shah stated that
Auspex hopes to complete a New Drug Application for HD and SD-809 during the
first half of this year. Review of such applications typically takes from six
to twelve months, depending on the circumstances.

“We have a huge sense
of urgency, especially given these [clinical trial] results, to do everything
we can to put the application together as soon as we possibly can,” Dr. Shah
emphasized.

Auspex has also
submitted for FDA approval a list of possibilities for SD-809’s eventual
commercial name.

On January 14, Auspex
received orphan drug designation from the FDA for use of SD-809 in Tourette
syndrome, another rare movement disorder.
The company is currently conducting a Tourette clinical trial.

Last year, Auspex
received the same designation for HD. Orphan drug status – for conditions
affecting fewer than 200,000 people in the U.S. – provides special incentives
for companies to produce drugs for these maladies.

Awaiting a price and
revenues

Dr. Shah said that
the company has not yet researched the price of the drug.

The exorbitant cost
of some orphan drugs has caused deep concern among affected families and
patient advocates. Lundbeck, which markets Xenazine, has a program to
assist HD families with the high cost of its drug, which can reach $50,000 at
the wholesale level for an annual supply (click here to read my previous article on the cost of orphan drugs).

“We remain committed
as a company to making SD-809 available to those who need it as much as we
can,” Dr. Shah commented.

As a young company
that only sold stock publicly for the first time in 2014, Auspex has yet to
generate revenues. Investors continue to support the company as it moves
forward with clinical trials and new research, Dr. Shah explained.

Xenazine will lose
its market exclusivity in August 2015 and become subject to generic
competition. This development could put additional pressure on Auspex to market
its drug affordably, but, at the same time, furnish the opportunity to stress
its compound’s greater safety.

New hope and a
platform for future research

“We haven’t had a positive study in HD in many,
many years, so it’s really an opportunity to celebrate a success that we’ve
seen here and to recognize that this is an important step forward for the field
and to kind of spread some good cheer and to have renewed hope for the field,”
Dr. Shah concluded about the SD-809 trial. “It is also important for the
community to remind the people who don’t know treating chorea does matter. It
can affect and does affect people’s quality of life.”

Auspex hopes to use
the SD-809 project as a platform for researching possible treatments that
attack the causes of HD, Dr. Shah said.

“We’re always on the
lookout for what makes sense to invest in there,” he added.

The success of the
drug and its acceptance by HD families and clinicians could help provide the
revenues needed to fund the new research into better remedies, he said.